Autologous peripheral blood stem cell transplantation (aPBSCT) is an effective treatment approach for patients with refractory or relapsed Hodgkin's Lymphoma (HL) and non-Hodgkin's Lymphoma (NHL). However, this treatment approach is associated with a high incidence of therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML), which is now recognized as a major cause of non-relapse mortality. Epidemiological studies indicate that stem cell damage from pre-transplant and transplant-related therapeutic exposures may contribute to the pathogenesis of t-MDS/AML following aPBSCT. However, the mechanisms underlying susceptibility to t-MDS/AML and the sequence of cellular and molecular abnormalities leading to transformation remain unknown. We have initiated a prospective, longitudinal evaluation of patients with HL/NHL undergoing aPBSCT. Patients are being followed longitudinally at multiple time-points from before aPBSCT to several years post-transplant, with serial collection and banking of blood and marrow samples, to allow investigation of factors that predict for the development of t-MDS/AML, and to follow the sequence of events leading to its development. This project will bring together investigators with expertise in epidemiology, DNA repair and hematopoiesis to investigate the hypothesis that pre-transplant and transplant-related therapeutic exposures in concert with defects in DNA repair mechanisms (Aim 1) and DNA damage response (Aim 2) are associated with development of detectable hematopoietic abnormalities (Aim 3) that antedate and predict for the development of t-MDS/AML among patients undergoing aPBSCT for HL/NHL. We will determine the sequence of acquisition of abnormalities in DNA repair mechanisms, DNA damage response, hematopoietic and cytogenetic abnormalities in the course of development of t-MDS/AML (Aim 4), and will investigate the potential role of the above abnormalities, therapeutic exposures and demographic variables in determining the risk of t-MDS/AML (Aim 5). Successful completion of these studies will provide insights into the pathogenesis of t-MDS/AML will allow accurate assessment of risk factors for t-MDS/AML following lymphoma therapy and detection of patients at early stages of leukemogenesis. Identification of biomarkers for HL and NHL patients at increased risk of development of t-MDS/AML, may aid modification of treatment regimens to reduce risk of this complication.